American Pediatric Society 2014 Presidential Address: the Thrill of Discovery (And Other Foundations of Biomedical Research)

Special Article nature publishing group

American Pediatric Society 2014 presidential address: the thrill of discovery (and other foundations of biomedical research)

Alan L. Schwartz1

nited States federal research funding has been on a down- discuss below. At Gilman’s retirement celebration, Woodrow Uward trend for the past decade. The thirty billion dollar Wilson, who earned his PhD at Hopkins in 1886, said, “In this, National Institutes of Health (NIH) budget is about 25% less in your greatest achievement, you established in America a new purchasing power today than it was a decade ago. What does and higher university ideal whose essential feature was…the this mean for our next generation? education of trained and vigorous minds through the search The belief that biomedical research pays a generous return for truth under the guidance and with the cooperation of mas- on investment is well-grounded, not only in dollars, but in lives ter investigators.” saved and illnesses mitigated. Nowhere is this more dramatic The history of “The Great American University, its rise to than in pediatrics. Witness the efficacy of vaccines in Table 1. preeminence, its indispensable national role and why it must A person born in the United States today will live about be protected” has been beautifully described by Jonathan R. 30 years longer than one born a century ago. Whenever one Cole, former Provost of Columbia University (1). hears about a biomedical research breakthrough in the United Johns Hopkins set the standard with a focus on the creation States, it is likely that National Institutes of Health (NIH) and/ of new knowledge via research. By 1900, discovery research, or other federal research dollars supported it. Yet, not alone. as well as teaching, began to be embraced by older, private, The academic medical centers are the fulcrum for those federal American universities, including Harvard, Columbia, the research dollars. Innovation at our academic medical centers University of Chicago, Cornell, Stanford, as well as several is one of the most critical cornerstones of American medicine. public institutions, such as the Universities of Michigan and “For decades, innovation has been fueled by federally funded Wisconsin. research that is conducted at universities across our nation.” In 1892, John D. Rockefeller established the University of says University of Wisconsin Chancellor, Rebecca Blank; Chicago led by William Rainey Harper. Harper entered college “America’s future economic prosperity depends on increased at 10 years of age, received his bachelor’s degree at 14 and a investments in research and education that will accelerate PhD at 18. He was a master of setting high standards, recruit- innovation and inspire future generations of scientists.” ing top faculty talent, and charting the course of excellence at The field of biomedicine has never been more dynamic; the the new University of Chicago. opportunities ahead nearly unlimited. Yet, academic medicine In 1901, Rockefeller founded the Rockefeller Institute of is under serious threat. The United States spent about 18% of Medical Research, now Rockefeller University; the first institu- its gross national product on healthcare last year. Universities’ tion in the United States devoted solely to biomedical research Schools of Medicine, and their associated teaching hospitals, and focused on understanding the underlying causes of disease. accounted for about 20% of these costs. Thus, in the United Simon Flexner, a Johns Hopkins trained pathologist, was States, the foundation for biomedical discovery research is Rockefeller’s first director. The Rockefeller Institute Hospital anchored within our research universities. opened in 1910 and was the first center for clinical research The first American university to emphasize research rather in the United States. Oswald T. Avery came to Rockefeller in than undergraduate teaching was Johns Hopkins, established 1913, and with Colin MacLeod and Maclyn McCarty in 1944, in 1876. Hopkins, who donated seven million dollars to build discovered DNA as the substance that transmits hereditary a new hospital and new type of university, had made his for- information (arguably one of the most important discoveries tune in real estate, banking, and railroads. Among the intel- not awarded a Nobel Prize). lectual leaders of this new university was Daniel Coit Gilman Throughout the second half of the 19th century, several who became the university’s first president and revolutionized other universities vacillated between strong commitments the idea of the American university. For Gilman, it was essen- to research and discovery, and to teaching. One fascinating tial that the faculty have the freedom to conduct research. One example is that of Yale. In 1854, the Yale Scientific School was of its earliest students was Thomas Hunt Morgan who we will created and soon became the Sheffield Scientific School. These

Presented at: The 2014 Annual Meeting of the American Pediatric Society, Vancouver, British Columbia, Canada. 1Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri. Correspondence: Alan L. Schwartz ([email protected]) Received 15 May 2014; accepted 19 May 2014; advance online publication 9 July 2014. doi:10.1038/pr.2014.81

316 Pediatric Research Volume 76 | Number 3 | September 2014 Copyright © 2014 International Pediatric Research Foundation, Inc. APS 2014 presidential address Special Article science students at Yale tended to be separate and nonequal. Vice President of Massachusetts Institute of Technology. They completed their degree in three, not the usual 4 years, Bush convinced President Roosevelt to create the National yet, had lower admission standards. Further, they were “not Defense Research Committee, which evolved into the Office permitted to sit with regular academic students in chapel.” of Scientific Research. Bush chaired the office and developed Despite this challenging start, “science schools”, which ulti- the blueprint for both the organization and the funding of mately grew into Science Departments, became a central part US research following World War II. Bush’s document, pre- of the development of the research intensive universities. sented to the President in July 1945, was entitled “Science At the beginning of the 20th century, universities began to – The Endless Frontier” (2). Among the key questions Bush widen their view beyond the liberal arts, law, medicine, and asked was, “How could medical research be encouraged?” He science. These full-service universities were criticized by none envisioned two types of science—basic and applied or “curios- other than Abraham Flexner, Simon Flexner’s brother, who, in ity-driven” and “mission-driven.” Then, as now, one difficulty 1910, evaluated the state of medical education in the United is apparent—can one fit medical or biological science neatly States and Canada. By the 1930’s, Flexner, who admired the into one of these categories. The efforts to develop therapies, focus at John Hopkins, was seriously concerned that American and ultimately to seek cures to diseases, invariably crosses the universities were insufficiently focused on the pursuit of new boundaries between the two. knowledge; that is, discovery. James B. Conant, Harvard’s President, summed up Bush’s By 1940, most of the key ingredients for the making of the innovative call for resources: “The essence of the revolution great American research universities were in place. As Cole was the shift from expanding research in government labora- notes, among these was the slow, but steady, movement from tories to the use of federal money to support work in universi- elitism to inclusion, where the doors of research intensive ties and scientific institutes.” universities now began to open to the talented among ethnic While the NIH, in fact, began in 1887 as a one-room labora- and religious groups, as well as to women. At the same time, tory of the Marine Service Hospital; in 1930, the Randall Act America’s research intensive universities began to establish changed its mission and renamed it as the National Institute of what were to become their shared core values, including orga- Health. Following World War II, the scale and scope of the NIH nized skepticism, creation of new knowledge, free and open dramatically expanded and extramural research grant support communication of ideas, the peer-review system, and intellec- began. In 1947, the new grants program awarded four million tual progeny. dollars. The major growth of NIH, from 1955 to 1968, under For one sterling example of the fertility of the research inten- its exceptional director, James Shannon, has been referred to sive universities, let us look to Thomas Hunt Morgan. Morgan as its “golden years.” Grant awards exceeded one billion dollars received his PhD in developmental biology at Johns Hopkins per year by 1970, ten billion dollars in 1993, and thirty billion in 1890. He joined the Columbia University faculty, in 1904, dollars in 2009 (Figure 1). where he began his studies of Drosophila biology, establishing The 1960’s saw another major innovation in America’s univer- his famous Fly Room. Among his many seminal discoveries, sities led by Clark Kerr, with his development of what he termed Morgan, in 1910, demonstrated the role of chromosomes in the “multiversity.” He described this in his 1963 Godkin lectures heredity, for which, in 1933, he received the Nobel Prize. at Harvard, “The Uses of the University.” The multiversity is a Throughout the 1930’s and 40’s, America’s research univer- system initially created in California with different schools, col- sities expanded rapidly. It was the era of the birth of big sci- leges, and universities integrated to fulfill a variety of missions. ence, led by physicists and chemists in part for the war effort. The pinnacle of this system was the major research universi- Among the key drivers of this effort was Vannevar Bush, ties, including University of California, Berkeley, University of

Table 1. Vaccine efficacy $31.3B 20th Century 2010 30 $31.0B annual reported % Disease morbidity cases Decrease 25 Smallpox 29,005 0 100%

Diphtheria 21,053 0 100% 20 $17.8B Pertussis 200,752 21,291 89% 15 Tetanus 580 8 99% $ (Billion)

Polio 16,316 0 100% 10 $7.6B Measles 530,217 61 >99% Mumps 162,344 2,528 98% 5 $3.4B $0.5M $0.7M $53M $0.4B $1.0B Rubella 47,745 6 >99% 0 Hemophilus influenza ~20,000 16 >99% 1938 1940 1950 1960 1970 1980 1990 2000 2010 2020 type b (<5 y old) Data obtained from http://www.cdc.gov/vaccines. Figure 1. National Institutes of Health funding.

California, Los Angeles, University of California, San Francisco, physician-scientists of our time, described his successive and thereafter, University of California, San Diego. Kerr’s vision research problems, and the challenges they presented, in his was that America’s economic welfare was critically dependent treatise “For the Love of Enzymes” (3). upon its ability to develop a highly educated population, as well Kornberg chose medicine, because he was an avid student as, an elite group of scientists who would produce ideas of sub- and, because in 1937, medical school provided an escape from stantial social value. This was certainly the case for half a cen- the depths of the Great Depression. His parents had immi- tury. Upon Kerr’s death in 2003, sociologist, Martin Trow, said grated from Eastern Europe in early 1900. His father was that “history will simply know him as the most distinguished a sewing machine operator in the Lower East Side of New university president of the 20th c e ntu r y.” York. Asked years later, by a biochemistry mentor, what did In Kerr’s final 1963 Godkin lecture, “The Future of the City of he collect as a child—butterflies, beetles? Kornberg replied, Intellect,” he emphasized that “the fastest growing intellectual “matchbooks”—it was the flora and fauna of his Brooklyn field today is biology. Here there is a veritable revolution.” “If streets and subways. After high school, and a New York State the first half of the 20th century may be said to have belonged Regents Scholarship, Kornberg entered City College of New to the physical sciences, the second half may well belong to the York and thereafter, the University of Rochester School of biological.” And so it has. Medicine. While he enjoyed studying medicine, he described The 1970s, 80s, and 90s witnessed an explosive growth of biochemistry as “rather dull”—a description of constituents of American medical schools, being reshaped into huge research- blood, tissue, and urine—the dynamism of macromolecules oriented enterprises. Many became “health science” centers. and energy metabolism was not yet known. Schools of Medicine, and their component departments, As a medical student, he noted a persistent mild yellow expanded dramatically in faculty size, research activity, and jaundice to the whites of his eyes. His bilirubin was well societal impact. The rapid and continuing advances, in scien- above normal levels. With an intolerance for fatty food, he tific knowledge, new technologies, and health-related research, was advised to have his gall bladder removed. To avoid it, he produced substantive changes in the Universities. At many, discovered seven other medical students with mild jaundice including my own, the School of Medicine became the largest, and elevated bilirubin like his. He then evaluated patients and often the most distinguished, School within the University. recovering from infectious hepatitis and assorted con- trols. His results, published as his first paper, “Latent Liver Let us pause for a moment... Disease in Persons Recovered from Catarrhal Jaundice and Close your eyes… in Otherwise Normal Medical Students as Revealed by the Bilirubin Excretion Test” appeared during his internal medi- Think of an example of a research university opening its cine internship in the 1942 Journal of Clinical Investigation. doors to a nascent young talent, providing the opportunity to This was the rediscovery of Gilbert’s disease (4), originally explore and to experience the thrill of discovery. described in the French literature in 1901. More importantly, I have many examples. Today, it is Arthur Kornberg, a this paper was read by the Army and Navy Medical Corps remarkable physician-scientist and biochemist. His discovery, and by Rolla Dyer, Director of the NIH, all of whom con- of the enzyme DNA polymerase and how it assembles DNA, tacted Kornberg as they were dealing with large numbers of earned him the Nobel Prize. Kornberg died, in 2007, at 89 World War II recruits who developed jaundice upon vaccina- (Figure 2). He had worked in his laboratory, at Stanford, up tion. Kornberg was given offers to join the tiny upstart NIH, until a few days before his death. In 2006, his son, Roger, was and the US Public Health Service, to begin his “training” in the Nobel laureate in Chemistry for his work on RNA poly- science. His first project (1944–1945) focused on nutritional merase. Arthur Kornberg, arguably one of the most important constituents and cofactors. After the War’s end, uninspired by his nutrition studies, he requested to spend a year learning biochemistry—he wanted to study enzymes and the source of adenosine triphosphate. While enzymes were known from the late 19th century’s studies of fermentation, their high catalytic potency was only just then being explored. NIH supported Kornberg to spend 18 months in two different enzymology laboratories—the first, via real serendipity, was a referral to work with a young, Spanish scientist who had escaped persecution in Europe and was given a bench at New York University in 1945. Severo Ochoa had just discovered that pigeon brain produced three molecules of adenosine triphosphate for each atom of oxygen consumed. Kornberg became Ochoa’s first trainee. Ochoa, it turns out, had studied earlier in Heidelberg with Meyerhoff, at Oxford with Peters, and at Washington University with Carl Figure 2. Arthur Kornberg, MD, Nobel Laureate. Reprinted with permission from the Stanford University Archives, Stanford, CA. Cori. We will come back to Ochoa later.

On his first day in the laboratory, Kornberg was presented and RNA synthesis—work done at Washington University the with six fresh pig hearts and charged with purifying the enzyme, previous 4 years. Significantly, he shared the Prize with Severo aconitase. With Ochoa, Kornberg learned the “philosophy and Ochoa, his mentor at New York University in 1946. practice of enzyme purification”—the basis of his life’s work. Kornberg went on to study dozens of enzymes of nucleic acid Purification allows one to remove contaminants and get at the biology. Purification was always step one. “Don’t waste clean true essence of an enzyme’s action, its function, and ultimately, thoughts on dirty enzymes” is one of his landmark phrases. its structure. It allows one to reconstitute nature in a test-tube. Stanford University owes much to Arthur Kornberg. It Over his lifetime, Kornberg purified and elegantly studied over was he, perhaps more than anyone else, who put Stanford 30 enzymes—one of which we will look at in a moment. He on the map in the medical and biological sciences, creating often said, “I never met a dull enzyme.” an environment that had a huge impact on all of biology, an After a year with Ochoa, Kornberg, in January 1947, came impact that went far beyond that of the work from his own to St. Louis to study with Ochoa’s mentor, Carl Cori. Cori and laboratory. He was an impassioned scientist, teacher, mentor, his wife, Gerty, had come to Washington University School and colleague. He wrote eloquently about biomedical science of Medicine in 1931; he as Professor of Pharmacology. The and its challenges. He felt that, to know and do science is not Cori’s had the wisdom to extend physiological studies, in ani- work—it is a privilege, and one is lucky to be able to do it. mals and tissues, to crude cell extracts and ultimately, to puri- Sometimes it is hard to remember that lesson, given the dif- fied enzymes. Kornberg would study the enzymatic origin of ficulties science dishes out. Doing biomedical science truly is inorganic pyrophosphate, a high energy metabolite in cellu- a privilege. lar energy generation. While the experiments were exciting, Kornberg was disappointed not to find the soluble enzyme Kornberg was a gifted, creative, and brilliant scientist. of adenosine triphosphate generation. It became clear, years later, that adenosine triphosphate was generated via the He stated, “What makes science unique is the discipline enzyme chain embedded in the insoluble mitochondria. Yet, rather than the practitioner. Verifiability and incremental Kornberg learned enzymology and the scientific method. One progress distinguish science from all other art forms.” month after Kornberg returned, from the Cori laboratory, to In his reflections on his life in science, Kornberg focused on the NIH, Carl and Gerty Cori were awarded the Nobel Prize the clinical investigator—“I can think of nothing more destruc- for their pioneering studies of glycogen metabolism and its tive of the productivity of the clinical investigator than a failure enzymology. to focus sharply on a single problem over a long space of time. Back at the NIH, Kornberg set up his own laboratory and The chief cause of this failure to advance knowledge is not a began studies on nucleotide pyrophosphatase. lack of effort, or motivation or opportunity. It is not a lack of Then in 1952, Washington University School of Medicine creativity, or intelligence, or training. The clinical investigator called and asked Kornberg to Head the new Department of fails when he lets problems choose and dominate him, rather Microbiology. In January 1953, Kornberg moved to St. Louis. than the reverse. The investigator must ask a small and modest Here, Kornberg established, arguably, the world’s most excit- question, focus on it in laser-beam fashion, and then maintain ing microbiology department. His recruits included Paul Berg, the focus until the beam burns through.” David Hogness, Robert Lehman, and Dale Kaiser. Equally Recently, with concern that America’s universities are at risk, important, Kornberg redirected his own work to the synthe- the US Congress asked the National Academies of Science to sis of DNA. As studying carbohydrate breakdown provided assess the competitive position of America’s research universi- insights into its synthesis, Kornberg hoped that studying DNA ties. Just over a year ago, the National Research Council of the breakdown would provide insights into its synthesis. A second US National Academies of Science released its study “Research insight was to pick a model system—he selected Escherichia Universities and the Future of America” (5). coli, the gut bacterium. In one classic Kornberg experiment, It begins, “America is driven by innovation—advances in he convinced the Grain Processing Corporation of Muscatine, ideas, products and processes that create new industries and Iowa, to use their 10,000 gallon vat to produce 200 lbs. of jobs, contribute to our nation’s health and security and support bacteria from which he isolated 500 mgs of pure DNA poly- a high standard of living. In the past half-century, innovation merase—a 200,000-fold purification—and that was in 1956! itself has been increasingly driven by educated people and the Five classic papers, in 1957–1958, on the enzymatic synthesis knowledge they produce. Our nation’s primary source of both of DNA resulted, as well as a detailed understanding of how new knowledge and graduates with advanced skills continues DNA replicates itself. to be our research universities.” In 1959, Kornberg was recruited to Stanford to serve as “American research universities are widely recognized as the Chairman and establish a new Department of Biochemistry. best in the world, admired for their education and research. For the past 50 years, it was likely the finest Department of They have the potential to drive innovation in areas important Biochemistry in the world. to America’s future including health and medicine.” That same year, October 1959, was also a landmark occasion Among today’s critical challenges, they note is that “young for Kornberg—he was awarded the Nobel Prize in Medicine for faculty have insufficient opportunities to launch academic his discovery of DNA polymerase and the mechanisms of DNA careers and research programs.”

comes the love of learning. That may sound trite, sentimen- tal, and self-serving, but nevertheless it is true. Research is an expression of faith in the possibility of progress. The drive that leads scholars to study a topic has to include the belief that new things can be discovered, that newer can be better, and that greater depth of understanding is achievable. Research, especially academic research, is a form of optimism about the human condition” (7). We must extoll that optimism about the human condition. The challenges are great, our Universities are strong, and our human talent is abundant. The economic climate is challenging; the political climate is challenging; the climate is challenging. Yet, the foundations of biomedical research are secure. Pediatrics needs you. Biomedicine needs you. Today’s and tomorrow’s children depend on you (Figure 3). Figure 3. Aegean Suite, by Judy Child. Reprinted with permission from Judy Child. STATEMENT OF FINANCIAL SUPPORT A.L.S. is the Harriet B. Spoehrer Professor of Pediatrics.

Last week, in PNAS Early Edition, Bruce Alberts, Marc References Kirshner, Shirley Tilghman, and Harold Varmus addressed 1. Cole JR. The Great American University, Its Rise To Preeminence, Its Indis- several of the issues which discourage many of today’s young pensable National Role, Why It Must Be Protected. USA: Public Affairs, trainees (6). Among their suggestions intended to stimulate 2009. debate are: bringing the biomedical enterprise into sustainable 2. Bush V. Science – The Endless Frontier. A Report to the President. Wash- ington: United States Government Printing Office, 1945. equilibrium and an increase in support for the best science 3. Kornberg A. For the Love of Enzymes: The Odyssey of a Biochemist. Harvard through federal grants. University Press, Cambridge, MA, USA, 1989. However this debate evolves, it is our research universi- 4. Kornberg A. Latent liver disease in persons recovered from catarrhal jaun- ties which educate the next generation of question-askers, dice and in otherwise normal medical students as revealed by the bilirubin those who will look differently at today’s problems and excretion test. J Clin Invest 1942;21:299–308. 5. Committee on Research Universities; Board on Higher Education and develop innovative solutions, and those who will confront Workforce (BHEW); Policy and Global Affairs (PGA); National Research tomorrow’s problems. We must provide as fertile a soil as Council. Research Universities and the Future of America: Ten Break- possible for their growth and development. The possibilities through Actions Vital to Our Nation’s Prosperity and Security. The are endless. National Academies Press, Washington, DC, 2012. Let me conclude with a quote from Henry Rosovsky, former 6. Alberts B, Kirschner MW, Tilghman S, Varmus H. Rescuing US biomedical research from its systemic flaws. Proc Natl Acad Sci USA Dean of the Faculty of Arts and Sciences at Harvard and author 2014;111:5773–7. of The University: An Owner’s Manual “In thinking about 7. Rosovsky H. The University: An Owner’s Manual. USA: Haddon what draws faculty to research, of uppermost importance Craftsmen, 1990.